446 research outputs found
Mice harbouring an oculodentodigital dysplasia-linked Cx43 G60S mutation have severe hearing loss
Given the importance of connexin43 (Cx43, encoded by GJA1) function in the central nervous system and sensory organ processing, we proposed that it would also be crucial in auditory function. To that end, hearing was examined in two mouse models of oculodentodigital dysplasia that globally express GJA1 mutations resulting in mild or severe loss of Cx43 function. Although Cx43(I130T/+) mutant mice, with similar to 50% Cx43 channel function, did not have any hearing loss, Cx43(G60S/+) mutant mice, with similar to 20% Cx43 channel function, had severe hearing loss. There was no evidence of inner ear sensory hair cell loss, suggesting that the mechanism for Cx43-linked hearing loss lies downstream in the auditory pathway. Since evidence suggests that Cx26 function is essential for hearing and may be protective against noise-induced hearing loss, we challenged Cx43(I130T/+) mice with a loud noise and found that they had a similar susceptibility to noise-induced hearing loss to that found in controls, suggesting that decreased Cx43 function does not sensitize the mice for environmentally induced hearing loss. Taken together, this study suggests that Cx43 plays an important role in baseline hearing and is essential for auditory processing. This article has an associated First Person interview with the first author of the paper
Double deletion of Panx1 and Panx3 affects skin and bone but not hearing
Pannexins (Panxs), large-pore channel forming glycoproteins, are expressed in a wide variety of tissues including the skin, bone, and cochlea. To date, the use of single knock-out mouse models of both Panx1 and Panx3 have demonstrated their roles in skin development, bone formation, and auditory phenotypes. Due to sequence homology between Panx1 and Panx3, when one Panx is ablated from germline, the other may be upregulated in a compensatory mechanism to maintain tissue homeostasis and function. To evaluate the roles of Panx1 and Panx3 in the skin, bone, and cochlea, we created the first Panx1/Panx3 double knock-out mouse model (dKO). These mice had smaller litters and reduced body weight compared to wildtype controls. The dKO dorsal skin had decreased epidermal and dermal area as well as decreased hypodermal area in neonatal but not in older mice. In addition, mouse skull shape and size were altered, and long bone length was decreased in neonatal dKO mice. Finally, auditory tests revealed that dKO mice did not exhibit hearing loss and were even slightly protected against noise-induced hearing damage at mid-frequency regions. Taken together, our findings suggest that Panx1 and Panx3 are important at early stages of development in the skin and bone but may be redundant in the auditory system. Key messages Panx double KO mice had smaller litters and reduced body weight. dKO skin had decreased epidermal and dermal area in neonatal mice. Skull shape and size changed plus long bone length decreased in neonatal dKO mice. dKO had no hearing loss and were slightly protected against noise-induced damage
Resetting the Abnormal Circadian Cortisol Rhythm in Adrenal Incidentaloma Patients With Mild Autonomous Cortisol Secretion
Context
Adrenal incidentalomas (AIs) are found commonly on axial imaging. Around 30% exhibit autonomous cortisol secretion (ACS) associated with increased cardiovascular events and death.
Objective
We hypothesized that AI/ACS patients have an abnormal cortisol rhythm that could be reversed by use of carefully timed short-acting cortisol synthesis blockade, with improvement in cardiovascular disease markers.
Design, Setting, and Participants
In a phase 1/2a, prospective study (Eudract no. 2012-002586-35), we recruited six patients with AI/ACS and two control groups of six sex-, age-, and body mass index–matched individuals: (1) patients with AI and no ACS (AI/NoACS) and (2) healthy volunteers with no AI [healthy controls (HC)]. Twenty-four-hour circadian cortisol analysis was performed to determine any differences between groups and timing of intervention for cortisol lowering using the 11β-hydroxylase inhibitor metyrapone. Circadian profiles of serum interleukin-6 (IL-6) were assessed.
Results
Serum cortisol levels in group AI/ACS were significantly higher than both group AI/NoACS and group HC from 6 PM to 10 PM [area under the curve (AUC) difference: 0.81 nmol/L/h; P = 0.01] and from 10 PM to 2 AM (AUC difference: 0.86 nmol/L/h; P < 0.001). In light of these findings, patients with ACS received metyrapone 500 mg at 6 PM and 250 mg at 10 PM, and cortisol rhythms were reassessed. Postintervention evening serum cortisol was lowered, similar to controls [6 PM to 10 PM (AUC difference: –0.06 nmol/L/h; P = 0.85); 10 PM to 2 AM (AUC difference: 0.10 nmol/L/h; P = 0.76)]. Salivary cortisone showed analogous changes. IL-6 levels were elevated before treatment [10 PM to 2 PM (AUC difference: 0.42 pg/mL/h; P = 0.01)] and normalized post treatment.
Conclusions
In AI/ACS, the evening and nocturnal cortisol exposure is increased. Use of timed evening doses of metyrapone resets the cortisol rhythm to normal. This unique treatment paradigm is associated with a reduction in the cardiovascular risk marker IL-6
Predictors of resolution and persistence of renal laboratory abnormalities in pediatric HIV infection
BACKGROUND: Among human immunodeficiency virus (HIV)-infected youth, the role of renal disease (RD) and its management has become increasingly important as these children/adolescents mature into young adults. The identification of predictors of abnormal renal laboratory events (RLE) may be helpful in the management of their HIV infection and its associated renal complications. METHODS: Data collected from HIV-infected youth followed for \u3e/= 48 months were analyzed to identify predictors of resolution versus persistence of RLE and determine the utility of RLE to predict the onset of RD. Analysis included descriptive and inferential methods using a multivariable extended Cox proportional hazards model. RESULTS: Of the 1,874 at-risk children enrolled in the study, 428 (23 %) developed RLE, which persisted in 229 of these (54 %). CD4 percentages of \u3c25 \u3e% [hazard ratio (HR) 0.63, p \u3c 0.002) and an HIV viral load of \u3e100,000 copies/ml (HR 0.31, p \u3c 0.01) were associated with reduced rates of resolution, while in most cases exposure to highly active antiretroviral therapy (HAART)/nephrotoxic HAART prior to or subsequent to RLE were not. Persistence of RLE was 88 % sensitive for identifying new RD. Negative predictive values for RD were \u3e95 % for both the at-risk cohort and those with RLE. CONCLUSIONS: Advanced HIV disease predicted persistence of RLE in HIV-infected youth. Persistent RLE were useful for identifying RD
Spectral Distortions of the CMB as a Probe of Inflation, Recombination, Structure Formation and Particle Physics
Following the pioneering observations with COBE in the early 1990s, studies
of the cosmic microwave background (CMB) have focused on temperature and
polarization anisotropies. CMB spectral distortions - tiny departures of the
CMB energy spectrum from that of a perfect blackbody - provide a second,
independent probe of fundamental physics, with a reach deep into the primordial
Universe. The theoretical foundation of spectral distortions has seen major
advances in recent years, which highlight the immense potential of this
emerging field. Spectral distortions probe a fundamental property of the
Universe - its thermal history - thereby providing additional insight into
processes within the cosmological standard model (CSM) as well as new physics
beyond. Spectral distortions are an important tool for understanding inflation
and the nature of dark matter. They shed new light on the physics of
recombination and reionization, both prominent stages in the evolution of our
Universe, and furnish critical information on baryonic feedback processes, in
addition to probing primordial correlation functions at scales inaccessible to
other tracers. In principle the range of signals is vast: many orders of
magnitude of discovery space could be explored by detailed observations of the
CMB energy spectrum. Several CSM signals are predicted and provide clear
experimental targets, some of which are already observable with present-day
technology. Confirmation of these signals would extend the reach of the CSM by
orders of magnitude in physical scale as the Universe evolves from the initial
stages to its present form. The absence of these signals would pose a huge
theoretical challenge, immediately pointing to new physics.Comment: Astro2020 Science White Paper, 5 pages text, 13 pages in total, 3
Figures, minor update to reference
Issues in solid-organ transplantation in children: translational research from bench to bedside
In this review, we identify important challenges facing physicians responsible for renal and cardiac transplantation in children based on a review of the contemporary medical literature. Regarding pediatric renal transplantation, we discuss the challenge of antibody-mediated rejection, focusing on both acute and chronic antibody-mediated rejection. We review new diagnostic approaches to antibody-mediated rejection, such as panel-reactive antibodies, donor-specific cross-matching, antibody assays, risk assessment and diagnosis of antibody-mediated rejection, the pathology of antibody-mediated rejection, the issue of ABO incompatibility in renal transplantation, new therapies for antibody-mediated rejection, inhibiting of residual antibodies, the suppression or depletion of B-cells, genetic approaches to treating acute antibody-mediated rejection, and identifying future translational research directions in kidney transplantation in children. Regarding pediatric cardiac transplantation, we discuss the mechanisms of cardiac transplant rejection, including the role of endomyocardial biopsy in detecting graft rejection and the role of biomarkers in detecting cardiac graft rejection, including biomarkers of inflammation, cardiomyocyte injury, or stress. We review cardiac allograft vasculopathy. We also address the role of genetic analyses, including genome-wide association studies, gene expression profiling using entities such as AlloMap®, and adenosine triphosphate release as a measure of immune function using the Cylex® ImmuKnow™ cell function assay. Finally, we identify future translational research directions in heart transplantation in children
Comparative health technology assessment of robotic-assisted, direct manual laparoscopic and open surgery:a prospective study
Background: Despite many publications reporting on the increased hospital cost of robotic-assisted surgery (RAS) compared to direct manual laparoscopic surgery (DMLS) and open surgery (OS), the reported health economic studies lack details on clinical outcome, precluding valid health technology assessment (HTA). Methods: The present prospective study reports total cost analysis on 699 patients undergoing general surgical, gynecological and thoracic operations between 2011 and 2014 in the Italian Public Health Service, during which period eight major teaching hospitals treated the patients. The study compared total healthcare costs of RAS, DMLS and OS based on prospectively collected data on patient outcome in addition to healthcare costs incurred by the three approaches. Results: The cost of RAS operations was significantly higher than that of OS and DMLS for both gynecological and thoracic operations (p < 0.001). The study showed no significant difference in total costs between OS and DMLS. Total costs of general surgery RAS were significantly higher than those of OS (p < 0.001), but not against DMLS general surgery. Indirect costs were significantly lower in RAS compared to both DMLS general surgery and OS gynecological surgery due to the shorter length of hospital stay of RAS approach (p < 0.001). Additionally, in all specialties compared to OS, patients treated by RAS experienced a quicker recovery and significantly less pain during the hospitalization and after discharge. Conclusions: The present HTA while confirming higher total healthcare costs for RAS operations identified significant clinical benefits which may justify the increased expenditure incurred by this approach
Photon noise from chaotic and coherent millimeter-wave sources measured with horn-coupled, aluminum lumped-element kinetic inductance detectors
We report photon-noise limited performance of horn-coupled, aluminum lumped-element kinetic inductance detectors at millimeter wavelengths. The detectors are illuminated by a millimeter-wave source that uses an active multiplier chain to produce radiation between 140 and 160 GHz. We feed the multiplier with either amplified broadband noise or a continuous-wave tone from a microwave signal generator. We demonstrate that the detector response over a 40 dB range of source power is well-described by a simple model that considers the number of quasiparticles. The detector noise-equivalent power (NEP) is dominated by photonnoise when the absorbed power is greater than approximately 1 pW, which corresponds to NEP ≈ 2×10^(−17) W Hz^(−1/2), referenced to absorbed power. At higher source power levels, we observe the relationships between noise and power expected from the photon statistics of the source signal: NEP∝P for broadband (chaotic) illumination and NEP∝P^(1/2) for continuous-wave (coherent) illumination
- …